KR20190105070A - Methods and pharmaceutical compositions for preventing or treating immunoinflammatory skin disorders - Google Patents

Abstract

A method of preventing or treating an immunoinflammatory skin disorder is provided. Also provided are pharmaceutical compositions for preventing or treating immunoinflammatory skin disorders.

Description

Methods and pharmaceutical compositions for preventing or treating immunoinflammatory skin disorders

The present invention relates to methods and pharmaceutical compositions for the prevention or treatment of immunoinflammatory dermal disorders.

Immunoinflammatory skin disorders include a variety of diseases, including autoimmune skin diseases, proliferative skin diseases, and inflammatory skin diseases. Immunoinflammatory skin disorders cause destruction of healthy tissue by inflammatory processes, dysregulation of the immune system, and unwanted cell proliferation.

Bullous pemphigoid (BP) is the most common blistering skin disease, which usually occurs in the elderly, usually in the late 70s, and in people over 80 years old. Increase substantially.

The pathogenesis of BP has been proposed to include complement activation, mast cell degranulation, recruitment and activation of neutrophils and eosinophils, and release of basement membrane zone (BMS) -degrading proteases from these effector cells.

The exact sequence of these events is little known, but one of the first steps in blister formation in BP is the autoantibodies targeting the hemismosomal transmembrane protein BP180, also known as collagen XVII (COL17). autoAb), which is believed to be the major autoantigen (autoAg) in the dermal-epidermal junction. After binding of NC16A, the extracellular domain of BP180, autoantibodies initiate Fc receptor-independent events that induce release of interleukin (IL) -6 and IL-8 from basal keratinocytes in a dose- and time-dependent manner. In addition, the combination of autoAb and BP180 induces BP180 internalization, which has been reported to play an important role in the initiation of BP disease pathogenesis [ Bullous Pemphigoid IgG Induces BP180 Internalization via a Macropinocytic Pathway, Hiroyasu et al, The American Journal of Pathology , Vol. 182, No. 3, March 2013, p828-840 ].

The inventors of the present application find that diacerein and / or berberine can inhibit the production of proinflammatory cytokines associated with BP180 internalization as well as immunoinflammatory skin disorders, and thus, immunoinflammatory skin disorders, in particular, It has been found that it may have therapeutic potential for BP.

In one embodiment, the invention is a method of preventing or treating an immunoinflammatory skin disorder, comprising a therapeutically effective amount of berberine or a biologically equivalent analogue of berberine or a pharmaceutically acceptable salt thereof in a subject in need thereof. Provided is a method comprising administering a pharmaceutical composition.

In another embodiment, the present invention provides a method of preventing or treating an immunoinflammatory skin disorder, the method of treating a subject in need thereof with a therapeutically effective amount of diacerane, rhein, monoacetylrhein, and salts thereof. Or a pharmaceutical composition comprising a compound selected from the group consisting of esters or prodrugs.

The invention also provides a pharmaceutical composition for preventing or treating an immunoinflammatory skin disorder, comprising a therapeutically effective amount of berberine or a biologically equivalent analogue of berberine or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical for the prevention or treatment of an immunoinflammatory skin disorder comprising a therapeutically effective amount of a diaserane, a lane, a monoacetyllane, and a compound selected from the group consisting of salts or esters or prodrugs thereof. To provide a composition.

1A is a statistical bar graph depicting the inhibitory effect of clobetasol propionate on the production of IL-6.
1B is a statistical bar graph depicting the inhibitory effect of clobetasol propionate on the production of IL-8.
2A is a statistical bar graph depicting the inhibitory effect of diacerane on the production of IL-6.
2B is a statistical bar graph depicting the inhibitory effect of diacerane on the production of IL-8.
3A is a statistical bar graph depicting the inhibitory effect of berberine on the production of IL-6.
3B is a statistical bar graph depicting the inhibitory effect of berberine on the production of IL-8.
4A is a statistical bar graph depicting the inhibitory effect of clobetasol propionate on mRNA production of IL-6 and IL-8.
4B is a statistical bar graph depicting the inhibitory effect of diacerein on mRNA production of IL-6 and IL-8.
4C is a statistical bar graph depicting the inhibitory effects of berberine on mRNA production of IL-6 and IL-8.
5A shows confocal microscopy of keratinocytes (right panel) and control (left panel; not treated with IgG) stained with fluorescent color (cell nucleus: dark blue; BP180: light green) and treated with IgG The picture is shown.
5B shows confocal microscopy images of keratinocytes stained with fluorescent color and treated with IgG.
5C shows confocal microscopy images of keratinocytes stained with fluorescent colors and treated with IgG and berberine at different concentrations.
FIG. 6A shows confocal microscopy images of keratinocytes (right panel) and controls (left panel; not treated with IgG) stained with fluorescent color and treated with IgG.
FIG. 6B shows confocal microscopy images of keratinocytes stained with fluorescent color and treated with IgG.
FIG. 6C shows confocal micrographs of keratinocytes stained with fluorescent color and treated with different concentrations of IgG and diacelein.

As used herein, the term “therapeutically effective amount” refers to an amount that alleviates or reduces one or more symptoms of a disease in at least one or more patients.

As used herein, the term “diacerein or analog thereof” refers to diacerane, lane, monoacetyllane, or a pharmaceutically acceptable salt or ester or prodrug thereof.

As used herein, the term “prodrug” refers to any compound that can be metabolized to its parent compound and exert its physiological function in the form of the parent compound in the body.

Unless otherwise stated herein, the singular terms ["a (an)", "the", etc.) used herein (in particular, in the following claims) should be understood to include both singular and plural forms. do.

Chemically, Lane is one of 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracene carboxylic acid and prodrugs thereof having the structure of formula (I) Is a 4,5-bis (acetyloxy) 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracenecarboxyl having a structure of formula (II) It is a mountain. Diacerane is completely converted to lanes before reaching the systemic circulation and exerts its physiological function in lane form in the body.

Formula (I)

Formula (II)

Diacerane is a widely used anti-inflammatory agent in the treatment of osteoarthritis, which has been demonstrated to inhibit interleukin-1 (IL-1) signaling. Currently, diacerane capsules are available in 50 mg concentrations and are available in various countries under various brand names including Art 50®, Artrodar®, and the like.

Berberine (Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo (g) -1,3-benzodioxolo (5,6-a) quinolizium) is a herbaceous plant, for example It is an isoquinoline alkaloid present in coptis (Coptidis rhizome), pewden (phellodenron), golden (Scutellaria baicalensis), Mahonia aquifolium and berberis. Berberine and its derivatives have been found to have antimicrobial and antimalarial activity. It can act on various classes of pathogens such as fungi, saccharomyces, parasites, bacterium and viruses.

The inventors of the present application have found that diacerein and berberine can inhibit the production of immunoinflammatory skin disorders, as well as proinflammatory cytokines associated with BP180 internalization, and can be used to treat such disorders. Accordingly, the present invention provides a method for preventing or treating an immunoinflammatory skin disorder, comprising a pharmaceutically effective amount of berberine or a biologically equivalent analogue of berberine or a pharmaceutically acceptable salt thereof in a subject in need thereof. It provides a method comprising administering a composition.

Biologically equivalent analogs of berberine in this method are, for example, jatrorrhizine, palmatine, coptisine, 9-demethylberberine, 9-demethyl Palminine (9-demethylpalmatine), 13-hydroyberberine, berberrubine, palmatrubine, 9-O-ethylberberubin, 9-O-ethyl-13-ethyl Berberubin, 13-methyldihydroberberine N-methyl salt, tetrahydroprotoberberine and its N-methyl salt, and 9-lauroylberberuline chloride.

Preferably, the pharmaceutically acceptable salt is berberine chloride.

In one embodiment, berberine or a biologically equivalent analogue of berberine or a pharmaceutically acceptable salt thereof is the main pharmaceutically active ingredient in the method.

In another embodiment, berberine or a biologically equivalent analogue of berberine or a pharmaceutically acceptable salt thereof is the only pharmaceutically active ingredient in the method.

The present invention also provides a method for preventing or treating an immunoinflammatory skin disorder, comprising: diacerane, lane, monoacetyllane, and salts or esters or prodrugs thereof in a subject in need thereof (ie, diacerane and its Analogs), the method comprising administering to the therapeutically effective amount a pharmaceutical composition comprising a compound selected from the group consisting of:

In one embodiment, the compound is diacerane.

In one embodiment, diacerane and analogs thereof are the main pharmaceutically active ingredient in the method.

In another embodiment, diacerane and analogs thereof are the only pharmaceutically active ingredient in the method.

In one embodiment, the therapeutically effective amount of the compound corresponds to 10-200 mg of diacerane base per day.

Preferably, the subject in the present invention is a human.

In one embodiment, the immunoinflammatory skin disorder is acute febrile neutrophilic dermatosis, dermatomyositis, exfoliative dermatitis, pompholyx, neutrophilic hidradenitis, sterile pustulosis, pruritic urticarial papules and plaques of pregnancy, bullous pemphigoid, pemphigus vulgaris, herpes Dermatitis herpetiforms, gestational pemphigoid gestationis, bowel-associated dermatosis-arthritis syndrome, rheumatoid neutrophilic dermatosis, and neutrophilic dermatosis of the dorsal hands, balanitis circumscripta plasmacellularis, balanoposthitis, Behcet's disease, erythema annulare centrifugum, erythema dyschromicum perstans, erythema multiforme, granuloma annulare, hand dermatitis, lichen nitidus, Lichen planus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen spinulosus, nummular dermatitis, pyoderma gangrenosum, sarco Sarcoidosis, subcorneal pustular dermatosis, urticaria, palmoplantar pustulosis, drug eruption, acute generalized exanthematous pustulosis, Contact dermatitis, and transient acantholytic dermatosis.

Preferably, the immunoinflammatory skin disorder is bullous swelling.

In the following, the invention will be further illustrated with reference to the following examples. However, these examples are provided merely to illustrate the purpose of the invention and not to limit the scope of the invention.

Example

Example 1 Cytokine Production Inhibition Study

The effect of diacerane or berberine to reduce anti-BP180 immunoglobulin G (IgG) -stimulated production of BP-related proinflammatory cytokines, IL-6 or IL-8 from human adult dermal keratinocytes, HaCaT cells Studied. Clobetasol propionate, a commonly used corticosteroid for treating BP as well as various other skin disorders, was used as a positive control.

IgG was purified from normal or BP patient blood. Accordingly, blood collection from healthy donors or BP patients was included in this study. Purified IgG was used to stimulate the production of proinflammatory cytokines such as IL-6 and IL-8 from HaCaT cells.

Blood collection

Patients treated at the Dermatology Department of the National Taiwan University Hospital (NTUH), have normal clinical findings, as well as IgG and / or IgG at the dermal-epidermal junction by direct immunofluorescence (DIF) microscopy. Documentation of the detection of circulating IgG autoantibodies against BP180 NC16A by linear deposits of C3 or enzyme-linked immunosorbent assay (ELISA) (MBL Co Ltd, Nagoya, Japan) The diagnosis of the BP based on the documentation should be obtained.

Blood was drawn twice from healthy volunteers as well as BP patients. The total amount of blood was 40 mL from healthy donor (s) or BP patient (s), with a maximum of 20 mL collected at one visit per subject.

Demographics including age, sex, medical history and diagnostic information including BP, and levels of circulating normal IgG, anti-BP180, or anti-BP230 IgG autoantibodies were recorded.

Blood samples were approved by NTUH's Research Ethics Committee (REC), and informed consent was obtained in accordance with the Declaration of Helsinki.

BP180- NC16A  Expression of protein

The BP180-NC16A expressing plasmid was provided by Professor Hiroshi Shimizu and Professor Wataru Nishie (Herukai University Graduate School of Medicine, Sapporo, Japan). Constructs encoding the NC16A domain (77 amino acids) were inserted into the MCS of the pGEX-6P1 vector. The plasmids were transformed with DH5a soluble cells and then DNA with the sequence identified as human BP180 NC16A was extracted. To obtain a large amount of NC16A protein, BL21 was transformed by introducing a plasmid, and then the NC16A domain protein was then expressed using the Overnight Express Autoinduction System (Novagen) according to the manufacturer's instructions.

IgG  refine

Total serum IgG from healthy blood donors (healthy-IgG) and patients diagnosed with BP (BP-IgG) were isolated using Hitrap Protein A HP column (GE Healthcare Life Sciences). Immunoglobulins were eluted with 0.1 M NaPi pH 8.0 (equilibrium), 0.1 M Na-citrate pH 6.0 (wash), and 0.1 M Na-citrate pH 3.0 (elution). Thereafter, the concentrated immunoglobulin is further eluted by a CNBr-activated Sepharose column coupled with BP180-NC16A protein (GE Healthcare Life Sciences) and isolated concentrated specific IgG that is responsive to NC16A. (Protein A Elu-NC16A-Elu). The immunoreactivity of the affinity-purified BP IgG preparations was confirmed by anti-BP180-NC16A ELISA (MBL Co Ltd, Nagoya, Japan).

Cell culture

HaCaT cells (CLS Cell Lines Service, Germany) were cultured in Dulbecco's Modified Eagle's Medium (DMEM) medium supplemented with 4.5 g / L glucose, 2 mM L-glutamine and 10% fetal calf serum. Cells were dispensed on 24-well or 12-well plates and grown to 80% confluence for the following assays.

Cell viability or cytotoxicity assessment

Exponentially growing cells of passages # 3 to 6 (3000 cells / well in 100 μl medium) were plated overnight in 96-well plates to attach cells (80% confluency), followed by 37 Diacerane (0.1, 1, 10 μM) or berberine (0.1, 1, 10 μM) or clobetasol propionate (0.1, 1, 10 μM) at different concentrations for 48 hours at < RTI ID = 0.0 > Exposure to either healthy-IgG, BP-IgG, or specific-IgG.

After drug treatment, the cell culture medium was carefully removed. Thereafter, the cells were carefully washed three times with warmed medium to remove isolated dead cells. Cells were incubated with MTT reagent at a final concentration of 1.0 mg / ml in cell culture medium for 2 hours. The amount of formazan (possibly directly proportional to the number of viable cells) was measured by recording the change in absorbance at 570 nm using an ELISA plate reader.

Proinflammatory Cytokine  Measure

Cytokine measurements were performed based on previous studies. Briefly, cells are incubated with medium alone, or with 2 mg / ml purified BP-IgG, or specific-IgG, and with dicerein or berberine or clobetasol propionate (0.1, 1, and 10). cultured in the absence or presence of μM) and culture supernatants were collected after 48 hours of incubation and stored at -20 ° C for analysis. IL-6 and IL-8 levels were analyzed in cell culture supernatants by ELISA (BD Biosciences) according to manufacturer's instructions.

IL-6 and IL-8 by Quantitative Real-Time Polymerase Chain Reaction mRNA  Quantification of Expression

IL-6 and IL-8 messenger RNA (mRNA) levels were quantified using quantitative real time polymerase chain reaction (qPCR) as previously reported. BP IgG-treated HaCaT cells were incubated with or without diaserine or berberine or clobetasol propionate for 48 hours. Total RNA was isolated from HaCaT cells cultured using TRIzol reagent (LifeTechnologies) according to manufacturer's instructions. Complementary DNA (cDNA) was reverse transcribed from isolated RNA by incubating 1 μg of RNA with the RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific) according to the manufacturer's instructions. Quantitative RT-PCR was performed in Mastercycler (Eppendorf) using SYBR® Select Master Mix (Life Technologies). The PCR mixture contained 0.5 μM of each forward primer and reverse buff primer, respectively. Each reaction mixture was treated for 2 minutes at 50 ° C and 2 minutes at 95 ° C, followed by 40 cycles of 15 seconds at 95 ° C and 1 minute at 60 ° C. The data was normalized with housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Primers used in RT-PCR are as follows: IL-8 messenger RNA (mRNA), forward 5'-ACC GGA AGG AAC CAT CTC AC-3 ', and reverse 5'-AAA CTG CAC CTT CAC ACA GAG-3 'And IL-6 messenger RNA (mRNA), forward 5'-GGT ACA TCC TCG ACG GCA TCT-3', and reverse 5'-GTG CCT CTT TGC TGC TTT CAC-3 'and GAPDH, forward 5'-ACA ACT TTG GTA TCG TGG AAG G-3 ′, and reverse 5′-GCC ATC ACG CCA CAG TTT-3 ′.

Statistical analysis

Data were analyzed using Student's t test or one-way analysis of variance (ANOVA). p values <0.05 were considered to represent statistically significant differences.

[result]

A total of 13 subjects were recruited during the study period. Six of these were normal controls and the other seven subjects were initially diagnosed with bullous swelling (BP). One of seven BP patients (case number 12) failed the screening due to negative DIF / IIF discovery. Case numbers 1, 2, 3, 4, and 13 had elevated circulating IgG autoantibodies against BP180 NC16A by ELISA.

A large amount of human NC16A protein was obtained using GST-Bulk kit and B-PER protein extraction reagent (Thermo), and cleavage of GST-tag was performed using the PreScission Protease system.

To isolate serum IgG from healthy blood donors (healthy-IgG) and patients diagnosed with BP (BP-IgG), using a Hitrap Protein A HP column, the concentrated immunoglobulin was combined with the CNBr- conjugated BP180-NC16A protein. Eluted further with an activated Sepharose column. Isolated efficiency was determined by relative fold change for IgG isolated from early stages (Protein A Elu) and enriched specific IgG (Protein A Elu-NC16A-Elu, ie specific-IgG) that is responsive to NC16A. It has the highest purified fold of specific IgG of up to 23.46 and 6821 IU / mg.

Keratinocyte cytotoxicity against different concentrations of diacerane, berberine or clobetasol propionate was assessed by MTT test. Diacerane treatments of 0.1 to 10 μM have reduced viability by 50% with significant cytotoxicity against HaCaT cells. Treatment with serum samples from healthy controls (healthy-IgG), BP-IgG or BP specific-IgG improved HaCaT viability by up to 250%, but 10 μM diacerane treatment still significantly reduced HaCaT viability. I was. In contrast, treatment with berberine and clobetasol propionate at 0.1-10 μM did not have significant cytotoxicity against HaCaT cells.

HaCaT cells were treated with 2 mg / ml purified BP-IgG or specific-IgG alone or with media at different concentrations (0, 0.1, 1, and 10 μM) of diacerane, berberine or clobetasol propionate. After incubation with, changes in IL-6 and IL-8 were tested and culture supernatants were collected after 48 hours of incubation. Clobetasol propionate, a positive control treatment, reduced IL-6 (FIG. 1A) and IL-8 secretion (FIG. 1B) in a dose-dependent manner. Diacerane significantly reduced the secretion of IL-6 in HaCaT cells treated with specific anti-BP180 IgG (FIG. 2A). In contrast, 0.1 μM of diacerane did not reduce the secretion of IL-8 in HaCaT cells treated with specific anti-BP180 IgG. The inhibitory effect of diacerane on IL-8 secretion was only seen at concentrations of 1 or 10 μM (FIG. 2B).

Berberine did not reduce the secretion of IL-6 in HaCaT cells treated with specific anti-BP180 IgG (FIG. 3A). Berberine reduced IL-8 secretion in HaCaT cells treated with BP specific-IgG. The inhibitory effect was significantly better in those cells treated with BP specific-IgG (FIG. 3B).

BP IgG-treated HaCaT cells were incubated with dicerane, berberine or clobetasol propionate at different concentrations (0, 0.1, 1, 10 μM) for 48 hours. Total RNA was isolated from cultured HaCaT cells and quantitative RT-PCR (RT-qPCR) analysis was performed. In the results, clobetasol propionate significantly reduced IL-6 and IL-8 mRNA expression levels (FIG. 4A), while diacerein had a dose dependent inhibitory effect on IL-6 mRNA expression levels. Only 10 μM was shown to have an inhibitory effect on IL-8 mRNA (FIG. 4B). In contrast, berberine has a dose-dependent inhibitory effect on both IL-6 and IL-8 mRNA expression (FIG. 4C).

The study indicates that diacerein and berberine have an inhibitory effect on the production of proinflammatory cytokines associated with immunoinflammatory skin disorders, and thus may have therapeutic potential for immunoinflammatory skin disorders.

[ Example  2] BP180 internalization research

BP180 is an important component of the antisolipid that keeps keratinocytes attached to the basal membranes of the skin. BP180 damage can lead to poor adhesion of keratinocytes and is associated with skin disorders or blister disease. BP180 internalization is considered to play an important role in the pathogenesis of bullous swelling, and thus can be measured for the assessment of these diseases. The following studies were performed to evaluate the effect of berberine, diaserane or lane on autoAbs (BP-IgG) -induced BP180 internalization and anti-diabetic breakdown in keratinocytes treated with BP-IgG.

How to: internalize BP180 Immunofluorescence  Research

For this BP180 internalization study, IgG tablets from BP patients and cell cultures treated with different IgGs and drugs (diacerein or berberine) were performed according to the procedure described in Example 1.

Keratin cells grown on glass coverslips were fixed in 4% paraformaldehyde, washed thoroughly in PBS, and infiltrated in 0.1% (v / v) Triton X-100 in PBS for 10 minutes. The primary antibody was overlaid on the skin and the preparation was incubated for 1 hour at room temperature. The skin on the coverslips was washed with PBS and fluorescent-conjugated secondary antibody was applied for 1 hour at room temperature. After washing with PBS, coverslips were mounted on slides. The fluorescent color for the cell nucleus was dark blue and light green at BP180. All preparations were tested by confocal microscopy.

[result]

Berberine  process

In control keratinocytes (ie not treated by IgG) and IgG treated keratinocytes from healthy subjects, immunofluorescence analysis (light green) of BP180 showed significant cytoplasmic and membrane localization (FIG. 5A). Conversely, membrane localization of BP180 in cells treated with BP-IgG was markedly reduced and showed greater spread in the cytoplasm, suggesting the occurrence of BP180 internalization induced by BP-IgG treatment and anti-oligode destruction ( 5b). As the berberine concentration increased (0.1-10 μM), the membrane localization of BP180 was restored, suggesting inhibition of BP180 internalization and maintenance of semi-integral integrity after berberine treatment (FIG. 5C).

Diacerane  process

Comparing control keratinocytes (ie not treated with IgG) and healthy-IgG treated keratinocytes (FIG. 6A), the BP180 distribution in the cell membrane is reduced and more diffuse in the cytoplasm of keratinocytes treated with BP-IgG. Which suggests the occurrence of BP180 internalization by BP-IgG treatment (FIG. 6B). As diacerane concentrations increased (0.1-10 μM), membrane localization of BP180 was restored, suggesting inhibition of BP180 internalization and maintenance of anti-diabetic integrity after diacerane treatment (FIG. 6C).

The results showed that diacerein and berberine can inhibit PB180 internalization and thus have therapeutic potential for BP.

The above disclosure relates to the detailed description and features of the invention. Those skilled in the art can make various modifications and substitutions based on the disclosures and suggestions of the invention as described without departing from the features of the invention.

Claims (16)

A method of preventing or treating an immunoinflammatory dermal disorder, comprising a therapeutically effective amount of berberine or a biologically equivalent analogue of berberine or a pharmaceutically acceptable salt thereof in a subject in need thereof. A method comprising administering a pharmaceutical composition. The method of claim 1, wherein the immunoinflammatory skin disorder is acute febrile neutrophilic dermatosis, dermatomyositis, exfoliative dermatitis, pompholyx, neutrophilic hidradenitis, sterile pustulosis, pruritic urticarial papules and plaques of pregnancy, bullous pemphigoid, pemphigus vulgaris, herpes Dermatitis herpetiforms, gestational pemphigoid gestationis, bowel-associated dermatosis-arthritis syndrome, rheumatoid neutrophilic dermatosis, and neutrophilic dermatosis of the dorsal hands, balanitis circumscripta plasmacellularis, balanoposthitis, Behcet's disease s disease, erythema annulare centrifugum, erythema dyschromicum perstans, erythema multiforme, granuloma annulare, hand dermatitis, lichen nitidus ), Lichen planus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen spinulosus, nummular dermatitis, pyoderma gangrenosum Sarcoidosis, subcorneal pustular dermatosis, urticaria, palmoplantar pustulosis, drug eruption, acute generalized exanthematous pustulosis ), Contact dermatitis, and transient acantholytic dermatosis. The method of claim 1, wherein said immunoinflammatory skin disorder is bullous swelling. The method of claim 1, wherein the biologically equivalent analogs of berberine are jatrorrhizine, palmatine, coptisine, 9-demethylberberine, 9-demethylpal. 9-demethylpalmatine, 13-hydroyberberine, berberrubine, palmatrubine, 9-O-ethylberberrubine, 9-O 9-O-ethyl-13-ethylberberrubine, 13-methyldihydroberberine N-methyl salt, tetrahydroprotoberberine and its N-methyl salt, and 9-lau Method selected from the group consisting of 9-lauroylberberrubine chloride. The method of claim 1, wherein the pharmaceutically acceptable salt is berberine chloride. The method of claim 1 wherein berberine or a biologically equivalent analogue of berberine or a pharmaceutically acceptable salt thereof is the main pharmaceutically active ingredient. The method of claim 1, wherein berberine or a biologically equivalent analog of berberine or a pharmaceutically acceptable salt thereof is the only pharmaceutically active ingredient. The method of claim 1, wherein the subject is a human. A method for preventing or treating an immunoinflammatory skin disorder, comprising: diacerein, rhein, monoacetylrhein, and salts or esters or prodrugs thereof in a subject in need thereof Administering a therapeutically effective amount of a pharmaceutical composition comprising the selected compound. 10. The method of claim 9, wherein the immunoinflammatory skin disorders are acute pyrogenic neutrophil dermatitis, dermatitis, exfoliative dermatitis, hanpoosis, neutropenia, aseptic pustules, pruritic urticaria and plaques during pregnancy, blistering oil Pelvic swelling, vulgaris ulcer, herpes dermatitis, gestational dermatitis, intestinal-associated dermatitis-arthritis syndrome, rheumatoid neutrophil dermatitis, neutrophil dermatitis on the back of hand, plasmacystic localized glansitis, glans foreskin, Behcet's disease, centrifugal annular erythema , Fixed dichroic erythema, polymorphic erythema, phantom granulomas, hand dermatitis, glossy thyroid, squamous thyroid, sclerotic atrophic thyroid, chronic simple thyroid, thyroid thyroid, molecular dermatitis, necrotizing pyoderma, sarcoidosis, subkeratoplasty, urticaria Selected from the group consisting of plantar abscesses, drug rashes, acute systemic rashes, contact dermatitis, and transient stromal dermatitis, Law. 10. The method of claim 9, wherein the immunoinflammatory skin disorder is bullous stools. The method of claim 9, wherein the compound is diacerane. The method of claim 9, wherein the compound is a major pharmaceutically active ingredient. The method of claim 9, wherein the compound is the only pharmaceutically active ingredient. The method of claim 9, wherein the subject is a human. The method of claim 9, wherein said therapeutically effective amount of said compound corresponds to 10 to 200 mg of diacerane base per day.

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